From Batch to Continuous Flow Synthesis in Enzymatic Process Towards Molnupiravir

Molnupiravir (1) is one among the limited therapeutic options for treating COVID-19 infection and exhibits pan-antiviral potency. Because of urgent demands during the COVID-19 pandemic, a number of methods were developed to offer more efficient routes. In this report, we present a facile 2-step and scalable synthesis of molnupiravir for batch processing and show the implementation of continuous flow biocatalysis to improve the efficiency in synthesis. Our key step entails immobilized lipase and isobutyric anhydride to facilitate regioselective esterification. In batch process, transamination of cytidine (2) provides N⁴-hydroxycytidine (NHC, 3) with 75 % yield followed by esterification of NHC to give molnupiravir with 64 % yield, providing 48 % overall yield and 99.98 % purity (HPLC). Compared to batch approach in the esterification step, the continuous flow process provides similar product yield and purity and highlights the advantages including 2.42-fold better productivity (mol/day), 2.47-fold improved reaction time, and 30-fold higher space-time-yield. The optimized batch and continuous flow biocatalysis enhance synthesis efficiency and reduce environmental impact, offering a sustainable approach for industrial molnupiravir production.